Understanding the mechanisms of limbic epileptogenesis may lead to novel disease modifying therapies. We have discovered that epileptogenesis is associated with enhanced activation of TrkB in the mossy fiber pathway of hippocampus. We have also discovered that the neurotrophin receptor, TrkB, is required for epileptogenesis in the kindling model. The objective of this application is to address two key questions: In what population of neurons within the mossy fiber pathway does the enhanced TrkB activation reside? Is the powerful antiepileptogenic effect of TrkB in the kindling model generalizable to other clinically relevant models? Morphological and electrophysiological studies of novel lines of genetically modified mice will be used to address these questions. We propose three Aims. To determine the cellular localization within the mossy fiber pathway of a surrogate measure of increased TrkB activation associated with limbic epileptogenesis. To determine whether inhibiting TrkB signaling prevents epileptogenesis in the pilocarpine status epilepticus model. To determine whether inhibiting TrkB signaling prevents epileptogenesis in the Kv1.1 -/- mouse. Successful completion of these Aims will provide valuable information for elucidating a cellular mechanism by which deletion of TrkB limits epileptogenesis. These experiments may also identify a novel molecular target for development of specific and effective anti-epileptogenic therapies. PUBLIC HEALTH RELEVANCE: Understanding the mechanisms of limbic epileptogenesis may lead to novel disease modifying therapies. We have discovered that epileptogenesis is associated with enhanced activation of TrkB in the mossy fiber pathway of hippocampus. We have also discovered that the neurotrophin receptor, TrkB, is required for epileptogenesis in the kindling model. We seek to determine whether inhibiting TrkB signaling prevents other types of epileptogenesis in animal models. This information will guide efforts aimed at exploiting TrkB as a molecular target for anti-epileptogenic therapies.